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Exposure to low ambient temperatures has previously been demonstrated to markedly improve glucose homeostasis in both rodents and humans. Although the brown adipose tissue is key in mediating these beneficial effects in rodents, its contribution appears more limited in humans. Hence, the exact tissues and underlying mechanisms that mediate cold-induced improvements in glucose homeostasis in humans remain to be fully established. In this review, we evaluated the response of the main organs involved in glucose metabolism (i.e. pancreas, liver, (white) adipose tissue, and skeletal muscle) to cold exposure and discuss their potential contribution to cold-induced improvements in glucose homeostasis in humans. We here show that cold exposure has widespread effects on metabolic organs involved in glucose regulation. Nevertheless, cold-induced improvements in glucose homeostasis appear primarily mediated via adaptations within the skeletal muscle and (presumably) white adipose tissue. Since the underlying mechanisms remain elusive, future studies should be aimed at pinpointing the exact physiological and molecular mechanisms involved in humans. Nonetheless, cold exposure holds great promise as a novel, additive lifestyle approach to improve glucose homeostasis in insulin resistant individuals.

Mesoporous silica particles (MSPs) can be used as food additives, clinically for therapeutic applications, or as oral delivery vehicles. It has also been discussed to be used for a number of novel applications including treatment for diabetes and obesity. However, a major question for their possible usage has been if these particles persist structurally and retain their effect when passing through the gastrointestinal tract (GIT). A substantial breaking down of the particles could reduce function and be clinically problematic for safety issues. Hence, we investigated the biostability of MSPs of the SBA-15 kind prepared at large scales (100 and 1000 L). The MSPs were orally administered in a murine model and clinically in humans. A joint extraction and calcination method was developed to recover the MSPs from fecal mass, and the MSPs were characterized physically, structurally, morphologically, and functionally before and after GIT passage. Analyses with N2 adsorption, X-ray diffraction, electron microscopy, and as a proxy for general function, adsorption of the enzyme α-amylase, were conducted. The adsorption capacity of α-amylase on extracted MSPs was not reduced as compared to the pristine and control MSPs, and adsorption of up to 17% (w/w) was measured. It was demonstrated that the particles did not break down to any substantial degree and retained their function after passing through the GITs of the murine model and in humans. The fact the particles were not absorbed into the body was ascribed to that they were micron-sized and ingested as agglomerates and too big to pass the intestinal barrier. The results strongly suggest that orally ingested MSPs can be used for a number of clinical applications. Validerad;2023;Nivå 2;2023-03-08 (joosat);Licens fulltext: CC BY License

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.

Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah−/−, Rag2−/−, Il2rg−/− mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.

Mesoporous silica particles (MSPs) are emerging as an interesting option to reduce calorific uptake as a treatment for obesity and other metabolic conditions. However, their further development under the pharmaceutical regulatory framework is hindered by poor understanding of the mechanisms by which they exert their effects. In the current study the interaction of MSPs with the lipid digestion process is investigated, specifically interactions with lipase enzymes and lipid digestion products as a key contributing factor to lipid absorption and calorific intake. The impact of exposing lipase to MSPs on the enzyme activity was assessed directly using the tributyrin digestion test. The extent of interaction of digestion products with MSPs was studied using selectively radiolabeled bile components and lipids, while the impact on in vivo absorption of lipids was studied by incorporation of radiolabelled lipid (triolein) into milk and administration with and without particles. The studies showed that particles that inhibited lipase activity also tended to interact more extensively with lipid digestion products. In vitro X-ray scattering studies revealed the interaction of some MSPs with lipid digestion products through changes in lipid self-assembly during digestion. The MSPs led to reduced lipid absorption in vivo compared to the control particles and MSP-free milk. While the specific properties of the MSPs that drive the differences between the behavior of MSPs during lipid digestion remain elusive, the studies highlight that interactions with the lipid digestion and absorption pathways are a likely mechanism for reducing calorific uptake.

beta(2)-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents, likely via mTORC2-mediated signalling. However, human data on this topic is virtually absent. We here investigate the effects of two-weeks treatment with the beta(2)-agonist clenbuterol (40 mu g/day) on glucose control as well as energy- and substrate metabolism in healthy young men (age: 18-30 years, BMI: 20-25 kg/m(2)) in a randomised, placebo-controlled, double-blinded, cross-over study (ClinicalTrials.gov-identifier: NCT03800290). Randomisation occurred by controlled randomisation and the final allocation sequence was seven (period 1: clenbuterol, period 2: placebo) to four (period 1: placebo, period 2: clenbuterol). The primary and secondary outcome were peripheral insulin-stimulated glucose disposal and skeletal muscle GLUT4 translocation, respectively. Primary analyses were performed on eleven participants. No serious adverse events were reported. The study was performed at Maastricht University, Maastricht, The Netherlands, between August 2019 and April 2021. Clenbuterol treatment improved peripheral insulin-stimulated glucose disposal by 13% (46.6 +/- 3.5 versus 41.2 +/- 2.7 mu mol/kg/min, p = 0.032), whereas skeletal muscle GLUT4 translocation assessed in overnight fasted muscle biopsies remained unaffected. These results highlight the potential of beta(2)-agonist treatment in improving skeletal muscle glucose uptake and underscore the therapeutic value of this pathway for the treatment of type 2 diabetes. However, given the well-known (cardiovascular) side-effects of systemic beta(2)-agonist treatment, further exploration on the underlying mechanisms is needed to identify viable therapeutic targets.beta 2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents. Here the authors report that two-weeks of treatment with the beta 2-agonist clenbuterol improves insulin-stimulated glucose disposal in healthy young men in a double-blinded, randomized cross-over trial.

Aims/hypothesis Chronic stimulation of β2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of β2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p −1 day−1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p p p p p Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective β2-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans.

Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15®, on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.

Objective The potential of brown adipose tissue (BAT) to influence energy homeostasis in animals and humans is encouraging as this tissue can increase fatty acid and glucose utilization to produce heat through uncoupling protein 1 (UCP1), but the actual mechanism of how the cell regulates glucose uptake is not fully understood. Myosin 1c (Myo1c) is an unconventional motor protein involved in several cellular processes, including insulin-mediated glucose uptake via GLUT4 vesicle fusion in white adipocytes, but its role in glucose uptake in BAT has not previously been investigated. Methods Using the specific inhibitor pentachloropseudilin (PClP), a neutralizing antibody assay, and siRNA, we examined the role of Myo1c in mechanisms leading to glucose uptake both in vitro in isolated mouse primary adipocytes and in vivo in mice. Results Our results show that inhibition of Myo1c removes insulin-stimulated glucose uptake in white adipocytes, while inducing glucose uptake in brown adipocytes, independent of GLUT4, by increasing the expression, translation, and translocation of GLUT1 to the plasma membrane. Inhibition of Myo1c leads to the activation of PKA and downstream substrates p38 and ATF-2, which are known to be involved in the expression of β-adrenergic genes. Conclusions Myo1c is a PKA repressor and regulates glucose uptake into BAT., Graphical abstract Image 1, Highlights • Myo1c is a BAT-specific regulator of glucose uptake. • Myo1c inhibition leads to increased expression, translation, and translocation of GLUT1. • Myo1c inhibition results in increased activation of PKA and its downstream targets.

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β2-/β3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, β2-adrenoceptor desensitization, β-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of β2-adrenoceptors, with a similar potency and efficacy to that of the nonselective β-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit β-arrestin1/2 to the β2-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a β2-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.

Prolonged supplementation with the beta(2)-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via beta(2)-adrenoceptor (beta(2)-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to-especially diabetic-humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to beta(1)- and beta(3)-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient (UCP1(-/-)) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1(-/-) C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1(-/-) C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in UCP1(-/-) mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1(-/-) mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, beta(2)-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans.NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged beta(2)-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the beta(2)-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1(-/-) mice, indicating that b2-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.

Prolonged supplementation with the β

The activation of thermogenesis in adipose tissue has emerged as an important target for the development of novel anti-obesity therapies. Using multi-well isothermal microcalorimetry, we have demonstrated that mature murine brown and brite adipocytes produce quantifiable heat upon β3-AR stimulation, independently of any anaerobic mechanisms. Additionally, in brite adipocytes lacking UCP1 protein, β3-AR stimulation still induces heat production, albeit to a much lower extent than in their wildtype counterparts, suggesting that UCP1 is an essential component of adrenergic induced thermogenesis in murine brite adipocytes exvivo. Similarly, we could observe an increase in heat production in human-derived adipocytes (hMADS) upon β-AR stimulation. Collectively, these results establish the use of isothermal microcalorimetry as a sensitive and accurate technique for measuring thermogenic responses in intact mature brite adipocytes from murine and human origin., Bokhari et al. demonstrate mature murine brown and brite adipocytes produce quantifiable heat with β3-AR stimulation. They indicate that the essential component of this mechanism is UCP1 by using adipocytes lacking the protein.

The β3 -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at β-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [3 H]-2-deoxyglucose uptake, cellular glycolysis, and O2 consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at β3 -adrenoceptors as they were largely absent in adipocytes derived from β3 -adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the β3 -adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the β3 -adrenoceptor.

The β3‐adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity‐related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at β‐adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron‐mediated effects were examined on cyclic AMP, UCP1 mRNA, [3H]‐2‐deoxyglucose uptake, cellular glycolysis, and O2 consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1‐mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at β3‐adrenoceptors as they were largely absent in adipocytes derived from β3‐adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the β3‐adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the β3‐adrenoceptor.

The standard of care for persons with prediabetes is lifestyle intervention, however in real-life less than 20% of people are able to adopt a healthier living. There is an unmet need for safe and effective treatment options for persons with prediabetes. We have developed unique mesoporous silica particles (MSP) with tailored characteristics (SiPore15) that sequesters pancreatic amylase and lipase locally in the gut, resulting in decreased digestion of carbohydrates and fats. A first-in-man safety-trial in healthy and obese volunteers (clinicaltrials.org ID no. NCT03667430) showed a good safety profile for SiPore15 and an exploratory analysis revealed a reduction in HbA1c. In the present efficacy-trial 43 subjects were enrolled, 33 persons with prediabetes (HbA1c 39 mmol/mol or above) and 10 persons newly diagnosed with diabetes type 2. All subjects were treated with SiPore15, 3 gm-TID with meals, for 12 weeks (clinicaltrials.org ID no. NCT03823027). A manufacturing error resulted in 26 subjects receiving the correct MSP for half of the treatment period and 9 subjects for the full period. An exploratory analysis revealed that the long-term blood glucose marker HbA1c was statistically reduced after 6 weeks (1 mmol/mol) and further reduced at 12 weeks (1.4 mmol/mol). Among the subjects who received the correct material, 0 subjects had a serious AE and the AEs reported were mild to moderate, indicating a favorable safety profile. The magnitude in HbA1c reduction was comparable to what has been observed with metformin in prediabetic clinical trials, translating to significant risk reduction in developing diabetes type 2. SiPore15’s novel ingestible device concept, combined with the preliminary demonstration of efficacy and safety indicates that SiPore15 is an exciting approach for prevention and treatment of diabetes and merits further clinical investigation. Disclosure E.V. Johnston: None. M.N. Iqbal: None. G. Robert-Nicoud: Employee; Self; Sigrid Therapeutics. M.Z. Lindgren: None. E.R. Waara: None. A. Udden: None. K. Pietiläinen: None. T. Bengtsson: Board Member; Self; Atrogi, Sigrid Therapeutics.

Aim: Obesity is a risk factor for cardiovascular disease and diabetes. We aimed to elucidate the effects of distinct mesoporous silica particles (MSPs) supplemented in food on metabolic parameters in obesity. Materials & methods: MSPs with precisely controlled pore size were synthesized, characterized and compared with a control in a C57Bl/6 mouse diet-induced obesity model, studying weight, adiposity, metabolic regulation and food efficiency. Results: The most effective MSPs reduced adipose tissue formation to 6.5 ± 0.5 g compared with 9.4 ± 1.2 g, leptin levels nearly halved from 32.8 ± 7.4 to 16.9 ± 1.9 ng/ml and a 33% reduction of food efficiency. Control MSP showed no effects. Conclusion: Results demonstrate potential of distinct MSPs to improve metabolic risk factors. Further studies investigating mechanism of action and confirming human safety are needed.

The β3 -adrenoceptor was initially an attractive target for several pharmaceutical companies due to its high expression in rodent adipose tissue, where its activation resulted in decreased adiposity and improved metabolic outputs (such as glucose handling) in animal models of obesity and Type 2 diabetes. However, several drugs acting at the β3 -adrenoceptor failed in clinical trials. This was thought to be due to their lack of efficacy at the human receptor. Recently, mirabegron, a β3 -adrenoceptor agonist with human efficacy, was approved in North America, Europe, Japan and Australia for the treatment of overactive bladder syndrome. There are indications that mirabegron may act at other receptors/targets, but whether they have any clinical relevance is relatively unknown. Besides overactive bladder syndrome, mirabegron may have other uses such as in the treatment of heart failure or metabolic disease. This review gives an overview of the off-target effects of mirabegron and its potential use in the treatment of other diseases. Linked articles This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

Uptake of glucose into skeletal muscle and adipose tissue plays a vital role in metabolism and energy balance. Insulin released from β-islet cells of the pancreas promotes glucose uptake in these target tissues by stimulating translocation of GLUT4 transporters to the cell surface. This process is complex, involving signaling proteins including the mechanistic (or mammalian) target of rapamycin (mTOR) and Akt that intersect with multiple pathways controlling cell survival, growth and proliferation. mTOR exists in two forms, mTOR complex 1 (mTORC1), and mTOR complex 2 (mTORC2). mTORC1 has been intensively studied, acting as a key regulator of protein and lipid synthesis that integrates cellular nutrient availability and energy balance. Studies on mTORC2 have focused largely on its capacity to activate Akt by phosphorylation at Ser473, however recent findings demonstrate a novel role for mTORC2 in cellular glucose uptake. For example, agonists acting at β2-adrenoceptors (ARs) in skeletal muscle or β3-ARs in brown adipose tissue increase glucose uptake in vitro and in vivo via mechanisms dependent on mTORC2 but not Akt. In this review, we will focus on the signaling pathways downstream of β-ARs that promote glucose uptake in skeletal muscle and brown adipocytes, and will highlight how the insulin and adrenergic pathways converge and interact in these cells. The identification of insulin-independent mechanisms that promote glucose uptake should facilitate novel treatment strategies for metabolic disease.

Mesoporous silica particles (MSPs) are thermally and chemically stable porous materials composed exclusively of silicon dioxide. Here we report the results of a First-in-Man clinical trial evaluating engineered MSPs with controlled surface area, pore volume, pore size, particle size and morphology, named SiPore, in obese but otherwise healthy male volunteers (n=20). SiPore is orally ingested and passes through the body without being absorbed and is safely eliminated via the feces. The clinical effects of SiPore were significant reduction in several metabolic and cardiovascular risk factors. HbA1c was reduced by 5% and LDL-C by 15% on average from baseline, both clinically meaningful reductions. Adverse events observed were mild and transient. These promising effects led to further investigations into SiPore’s mode of action. We hypothesized that SiPore acts as a molecular sieve by sequestration of biomolecules in the gastrointestinal tract, which could explain the observed clinical results. This merited a more detailed analysis of the interaction between SiPore and digestive enzymes. SiPore significantly sequestered amylase and lipase in vitro while MSPs with smaller pore size had no effect. Lipase and amylase were depleted by SiPore from more complex biological matrices, such as porcine pancreatin and mouse intestinal fluid. Moreover, SiPore inhibited the activity of human salivary amylase in human saliva. Further studies of amylase depletion in vitro indicated that the availability of pores of a certain pore size is a critical parameter for enzyme sequestration. This innovative mode of action, combined with SiPore’s promising safety profile, makes SiPore an exciting candidate for treatment or prevention of metabolic diseases, particularly prediabetes and type 2 diabetes (T2D). SiPore is currently being investigated in an ongoing clinical trial in 40 prediabetic or newly diagnosed T2D subjects (NCT03823027). Disclosure M.E. Lindgren: Employee; Self; Sigrid Therapeutics AB. E. Rollman Waara: Employee; Self; Sigrid Therapeutics AB. B. Benziane: Employee; Self; Sigrid Therapeutics. H. Vallhov: Employee; Self; Sigrid Therapeutics. N. Iqbal: None. E.V. Johnston: None. T. Bengtsson: Other Relationship; Self; Atrogi, Sigrid Therapeutics. Funding Vinnova (2015-02023)

Adrenoceptors play an important role in adipose tissue biology and physiology that includes regulating the synthesis and storage of triglycerides (lipogenesis), the breakdown of stored triglycerides (lipolysis), thermogenesis (heat production), glucose metabolism, and the secretion of adipocyte-derived hormones that can control whole-body energy homeostasis. These processes are regulated by the sympathetic nervous system through actions at different adrenoceptor subtypes expressed in adipose tissue depots. In this review, we have highlighted the role of adrenoceptor subtypes in white, brown, and brite adipocytes in both rodents and humans and have included detailed analysis of adrenoceptor expression in human adipose tissue and clonally derived adipocytes. We discuss important considerations when investigating adrenoceptor function in adipose tissue or adipocytes. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β

BackgroundPrecisely engineered mesoporous silica has been shown to induce weight loss in mice, but whether it is safe to use in humans have not investigated.ObjectiveThe aim was to determine whether oral dosing, up to 9 grams/day, of precisely engineered mesoporous silica as a food additive can be used safely in male humans.DesignThis single blinded safety study consisted of two study arms including 10 males each (18-35 years). One arm consisted of participants with normal weight and one with obesity. After a placebo run-in period, all subjects were given porous silica three times daily, with increasing dose up to 9 grams/day (Phase 1). Subjects with obesity continued the study with highest dose for additional 10 weeks (Phase 2).ResultsAll participants completed Phase 1 and 90% completed Phase 2, with approximately 1% missed doses. Participants reported no abdominal discomfort, and changes in bowel habits were minor and inconsistent. The side effects observed were mild and tolerable, biomarkers did not give any safety concern, and no severe adverse events occurred.ConclusionMesoporous silica intake of up to 9 grams/day can be consumed by males without any major adverse events or safety concerns.

Engineered mesoporous silica particles (MSP) are thermally and chemically stable porous materials composed of pure silica and have attracted attention for their potential biomedical applications. Oral intake of engineered MSP is shown to reduce body weight and adipose tissue in mice. Here, clinical data from a first-in-humans study in ten healthy individuals with obesity are reported, demonstrating a reduction in glycated hemoglobin (HbA1c) and low-density lipoprotein cholesterol, which are well-established metabolic and cardiovascular risk factors. In vitro investigations demonstrate sequestration of pancreatic α-amylase and lipase in an MSP pore-size dependent manner. Subsequent ex vivo experiments in conditions mimicking intestinal conditions and in vivo experiments in mice show a decrease in enzyme activity upon exposure to the engineered MSP, presumably by the same mechanism. Therefore, it is suggested that tailored MSP act by lowering the digestive enzyme availability in the small intestine, resulting in decreased digestion of macronutrient and leading to reduced caloric uptake. This novel MSP based mechanism-of-action, combined with its excellent safety in man, makes it a promising future agent for prevention and treatment of metabolic diseases.

A vital role of adrenoceptors in metabolism and energy balance has been well documented in the heart, skeletal muscle, and adipose tissue. It has been only recently demonstrated, however, that activation of the mechanistic target of rapamycin (mTOR) makes a significant contribution to various metabolic and physiological responses to adrenoceptor agonists. mTOR exists as two distinct complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) and has been shown to play a critical role in protein synthesis, cell proliferation, hypertrophy, mitochondrial function, and glucose uptake. This review will describe the physiological significance of mTORC1 and 2 as a novel paradigm of adrenoceptor signalling in the heart, skeletal muscle, and adipose tissue. Understanding the detailed signalling cascades of adrenoceptors and how they regulate physiological responses is important for identifying new therapeutic targets and identifying novel therapeutic interventions. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

The recruitment of brite (or beige) adipocytes has been advocated as a means to combat obesity, due to their ability to phenotypically resemble brown adipocytes (BA). Lineage studies indicate that brite adipocytes are formed by differentiation of precursor cells or by direct conversion of existing white adipocytes, depending on the adipose depot examined. We have systematically compared the gene expression profile and a functional output (oxygen consumption) in mouse adipocytes cultured from two contrasting depots, namely interscapular brown adipose tissue, and inguinal white adipose tissue (iWAT), following treatment with a known browning agent, the peroxisome proliferator-activated receptor (PPARγ) activator rosiglitazone. Prototypical BA readily express uncoupling protein (UCP)1, and upstream regulators including the β3-adrenoceptor and transcription factors involved in energy homeostasis. Adipocytes from inguinal WAT display maximal UCP1 expression and mitochondrial uncoupling only when treated with a combination of the PPARγ activator rosiglitazone and a β3-adrenoceptor agonist. In conclusion, brite adipocytes are fully activated only when a browning agent (rosiglitazone) and a thermogenic agent (β3-adrenoceptor agonist) are added in combination. The presence of rosiglitazone throughout the 7-day culture period partially masks the effects of β3-adrenoceptor signaling in inguinal white adipocyte cultures, whereas including rosiglitazone only for the first 3 days promotes robust β3-adrenoceptor expression and provides an improved window for detection of β3-adrenoceptor responses.

There are two types of adipose tissue with distinct functions-white adipose tissue stores chemical energy as triglycerides, whereas brown adipose tissue consumes energy and releases heat (thermogenesis) in response to sympathetic nerve activity. In humans, treatments that promote greater brown adipose tissue deposition and/or activity would be highly beneficial in regimes aimed at reducing obesity. Adult humans have restricted populations of prototypical brown adipocytes in the neck and chest areas, but recent advances have established that adipocytes with similar properties, termed "brite" adipocytes, can be recruited in subcutaneous depots thought to be primarily white adipose tissue. These brite adipocytes express the protein machinery required for thermogenesis, but to assess brite adipocytes as viable therapeutic targets we need to understand how to promote conversion of white adipocytes to brite adipocytes and ways to increase optimal energy consumption and thermogenesis in these brite adipocytes. This can be accomplished by pharmacological and nutritional therapies to differing degrees, as reviewed in detail here.

The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the α

Recruitment and activation of brite (or beige) adipocytes has been advocated as a potential avenue for manipulating whole-body energy expenditure. Despite numerous studies illustrating the differences in gene and protein markers between brown, brite and white adipocytes, there is very little information on the adrenergic regulation and function of these brite adipocytes. We have compared the functional (cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, extracellular acidification rates, calcium influx) profiles of mouse adipocytes cultured from three contrasting depots, namely interscapular brown adipose tissue, and inguinal or epididymal white adipose tissues, following chronic treatment with the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone. Prototypical brown adipocytes readily express β3-adrenoceptors, and β3-adrenoceptor stimulation increases cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, and extracellular acidification rates. Treatment of brown adipocytes with rosiglitazone increases uncoupling protein 1 (UCP1) levels, and increases β3-adrenoceptor mitochondrial function but does not affect glucose uptake responses. In contrast, inguinal white adipocytes only express UCP1 and β3-adrenoceptors following rosiglitazone treatment, which results in an increase in all β3-adrenoceptor-mediated functions. The effect of rosiglitazone in epididymal white adipocytes, was much lower compared to inguinal white adipocytes. Rosiglitazone also increased α1-adrenoceptor mediated increases in calcium influx and glucose uptake (but not mitochondrial function) in inguinal and epididymal white adipocytes. In conclusion, the PPARγ agonist rosiglitazone promotes the induction and function of brite adipocytes cultured from inguinal and epididymal white adipose depots.

Objective Today, the presence and activity of brown adipose tissue (BAT) in adult humans is generally equated with the induced accumulation of [2-18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) in adipose tissues, as investigated by positron emission tomography (PET) scanning. In reality, PET-FDG is currently the only method available for in vivo quantification of BAT activity in adult humans. The underlying assumption is that the glucose uptake reflects the thermogenic activity of the tissue. Methods To examine this basic assumption, we here followed [18F]FDG uptake by PET and by tissue [3H]-2-deoxy-d-glucose uptake in wildtype and UCP1(−/−) mice, i.e. in mice that do or do not possess the unique thermogenic and calorie-consuming ability of BAT. Results Unexpectedly, we found that β3-adrenergically induced (by CL-316,243) glucose uptake was UCP1-independent. Thus, whereas PET-FDG scans adequately reflect glucose uptake, this acute glucose uptake is not secondary to thermogenesis but is governed by an independent cellular signalling, here demonstrated to be mediated via the previously described KU-0063794-sensitive mTOR pathway. Conclusions Thus, PET-FDG scans do not exclusively reveal active BAT deposits but rather any tissue possessing an adrenergically-mediated glucose uptake pathway. In contrast, we found that the marked glucose uptake-ameliorating effect of prolonged β3-adrenergic treatment was UCP1 dependent. Thus, therapeutically, UCP1 activity is required for any anti-diabetic effect of BAT activation., Graphical abstract Image 1, Highlights • β3-adrenergically glucose uptake in BAT is UCP1-independent. • Glucose uptake is not secondary to thermogenesis but is through the mTOR pathway. • Both glucose uptake and thermogenesis are needed to fully effect glucose homeostasis.